In 2017, after undergoing a minimally invasive surgery to remove a blood clot above his left eye, a tissue sample revealed the presence of brain cancer.
His office said in a statement that he died Saturday at 4:28 p.m. local time at his ranch near Sedona, AZ.
"Our family is immensely grateful for the support and kindness of all his caregivers over the a year ago, and for the continuing outpouring of concern and affection from John's many friends and associates, and the many thousands of people who are keeping him in their prayers", the family's statement concluded.
They said he chose to stop his treatment "with his usual strength of will".
"The entire McCain family is overwhelmed by the outpouring of love and support from around the world".
"The days and years to come will not be the same without my dad - but they will be good days, filled with life and love, because of the example he lived for us", she wrote in a statement shared on Twitter. One of his rescuers said many years later that McCain was well treated after being pulled from the lake by villagers.
"I just knew it wasn't the right thing to do", he is later reported to have said. "Now, we're going to do what we can, get the best doctors we can find, and do the best we can".
But it would be another two years before McCain first emerged onto the national stage.
Former vice-president Joe Biden, who developed a friendship with McCain while they served together in the Senate, said the Arizona lawmaker will "cast a long shadow".
"He passed the way he lived, on his own terms, surrounded by the people he loved, in the the place he loved best", McCain's widow Cindy wrote on Twitter. Biden's son Beau died in 2015 after fighting glioblastoma.
During a recent appearance by former Vice President Joe Biden, who is promoting his new book, "Promise Me, Dad: A Year of Hope, Hardship and objective", the Democrat lauded Meghan's father and offered words of encouragement. The dramatic move shocked his fellow Republicans, who thought repeal was a done deal.
"Before I leave, I'd like to see our politics begin to return to the purposes and practices that distinguish our history from the history of other nations". "We don't need more bullying, and I'm exhausted of it!"
China Trade Talks End With No Sign of Progress
And as China has vowed to retaliate further, Trump has threatened to target all $500 billion in goods the U.S. imports. The list of USA products this time includes oil products and coal for the first time, S&P Global Platts reports .
Trump and McCain were at odds until the end.
McCain found Putin's growing influence on the world stage particularly worrisome.
McCain also frequently and directly criticized the commander in chief himself.
A Vietnam POW and a known defense hawk, McCain lost his bid for the White House to Barack Obama in 2008.
Justice Minister Ayelet Shaked said McCain was "one of Israel's biggest friends".
The late senator requested that both Obama and Bush deliver eulogies at his funeral, U.S. media reported. McCain said. "Merely preventing your political opponents from doing what they want isn't the most inspiring work".
He attended 20 different schools on his way to graduating from a private boarding school in Virginia in 1954.
McCain's plane was shot down during a bombing run over North Vietnam in 1967, and he parachuted into a lake in what is now a busy part of Hanoi. McCain deployed his parachute and plunged into a lake, breaking his leg and both arms.
While holding him as a prisoner of war, the North Vietnamese tried to exploit the fact that his father was a prominent admiral at the time.
McCain spent more than 3 decades in the Senate, looming large in debates over war and peace and the moral direction of the nation. He was refused medical treatment and beaten with a bayonet. He was released in 1973.
But long before then, McCain was a Navy brat who had little interest in being studious. His naval honors include the Silver Star, Bronze Star, Legion of Merit, Purple Heart, and the Distinguished Flying Cross. He was elected to Congress in 1982 and to the Senate four years later, replacing the retired Barry Goldwater.
The governor of Arizona, Doug Ducey, will appoint a replacement for McCain, and by state law the appointee must be from the same party - in this case, a Republican.